The long-range objective of this Program Project is to engender a better understanding of the factors that contribute to heightened susceptibility to smoking and nicotine dependence, using a Nicotine Research Consortium as the vehicle for coordinating and sustaining research activity derived from several independent NIH projects. Specific aims are (a) to identify highly heritable, latent factors (endophenotypes) to characterize the course and causes of smoking behavior more accurately; (b) to use twin genetic methods to estimate the heritability (proportion of variance accounted for) of endophenotypes; and (c) to test endophenotypes for association with particular candidate genes. Systematic investigations will be carried out using both biometric and measured genetic approaches in the context of three related projects: Project A, Behavioral genetics of nicotine reactivity, will attempt to quantify the genetic contribution to nicotine-dependent smoking in concordant and discordant (monozygotic and dizygotic; MZ/DZ) twins and their siblings, focusing on initial sensitivity to nicotine and chronic tolerance as phenotypic indicators. Project B, Behavioral phenotypes and environmental factors for tobacco use, examines the contribution of genetic and environmental sources of variation for smoking along dimensions of dependence, lifetime tobacco use milestones and trajectories, and composite phenotypes in a series of psychometric studies and behavior genetic studies in concordant and discordant MZ/DZ twins, in order to identify endophenotypes. Project C, Candidate genes for smoking in related and unrelated individuals, will involve an examination of ~60 susceptibility genes for smoking in (a) unrelated smokers and never-smokers using a case-control design and (b) in smokers and their biological parents using a parent-child trio design to determine genetic association with endophenotypes identified in Projects A and B. Three cores support the activities of the projects: The Administrative Core, the coordinating center for the Nicotine Research Consortium, is responsible for communication, integration, and quality control. The Analytical Chemistry Core will conduct analyses of biological samples (nicotine, cotinine, hydroxy-cotinine) from each project. The Data Management and Analysis Core will provide organized statistical design, warehousing of phenotype and genotype data, and advanced genetic analyses. Health relatedness. The proposed Program Project constitutes a systematic investigation of how individual biological, behavioral, and environmental factors come together and interact to create tobacco dependence. Identification of environmental and behavioral risk factors and more accurate characterization of phenotypes and genotypes for smoking constitute crucial next steps in the elucidation of underlying mechanisms for smoking. Such knowledge will confer new insights about the etiology and progression of smoking and should improve the current understanding of smoking, which is still largely descriptive.